GLI3

GLI family zinc finger 3, the group of Zinc fingers C2H2-type

Basic information

Region (hg38): 7:41960949-42264100

Previous symbols: [ "GCPS", "PHS" ]

Links

ENSG00000106571 ∙ NCBI:2737 ∙ OMIM:165240 ∙ HGNC:4319 ∙ Uniprot:P10071 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Greig cephalopolysyndactyly syndrome (Definitive), mode of inheritance: AD
• polydactyly, postaxial, type A1 (Definitive), mode of inheritance: AD
• Pallister-Hall syndrome (Definitive), mode of inheritance: AD
• Greig cephalopolysyndactyly syndrome (Strong), mode of inheritance: AD
• Greig cephalopolysyndactyly syndrome (Strong), mode of inheritance: AD
• Pallister-Hall syndrome (Definitive), mode of inheritance: AD
• Greig cephalopolysyndactyly syndrome (Definitive), mode of inheritance: AD
• polysyndactyly 4 (Moderate), mode of inheritance: AD
• acrocallosal syndrome (Supportive), mode of inheritance: AR
• Greig cephalopolysyndactyly syndrome (Supportive), mode of inheritance: AD
• Pallister-Hall syndrome (Supportive), mode of inheritance: AD
• tibial hemimelia (Supportive), mode of inheritance: AD
• postaxial polydactyly type A (Supportive), mode of inheritance: AR
• polysyndactyly 4 (Supportive), mode of inheritance: AD
• Greig cephalopolysyndactyly syndrome (Definitive), mode of inheritance: AD
• Pallister-Hall syndrome (Definitive), mode of inheritance: AD
• Greig cephalopolysyndactyly syndrome (Strong), mode of inheritance: AD
• Pallister-Hall syndrome (Strong), mode of inheritance: AD
• polydactyly, postaxial, type A1 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pallister-Hall syndrome	AD	Endocrine	Urgent treatment for endocrine abnormalities may be required; Surgical interventions related to hypothalamic hamartoma may be indicated	Craniofacial; Endocrine; Musculoskeletal; Neurologic	4317883; 7211952; 6295159; 6641002; 2596511; 1650914; 9054938; 9042919; 9302279; 10441570; 10945658; 10678662; 12794692; 14608643; 15811011; 15739154; 18000979; 18435847; 20301619; 20301638; 20503312; 20583172; 20672375; 21108399; 21320477; 21326280; 22428873; 23633388; 24736735

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GLI3 gene.

• Greig cephalopolysyndactyly syndrome;Pallister-Hall syndrome (30 variants)
• not provided (24 variants)
• Pallister-Hall syndrome;Greig cephalopolysyndactyly syndrome (21 variants)
• Greig cephalopolysyndactyly syndrome (13 variants)
• Polydactyly, postaxial, type A1 (7 variants)
• Pallister-Hall syndrome (5 variants)
• Polysyndactyly 4 (3 variants)
• Inborn genetic diseases (3 variants)
• GLI3-related disorder (2 variants)
• Postaxial polydactyly, type A1/B (1 variants)
• Pallister-Hall syndrome;Greig cephalopolysyndactyly syndrome;Polysyndactyly 4;Polydactyly, postaxial, type A1 (1 variants)
• Abnormality of prenatal development or birth (1 variants)
• Craniosynostosis syndrome (1 variants)
• Greig cephalopolysyndactyly syndrome;Polydactyly, postaxial, type A1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GLI3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	152	38	199
missense	1	5	274	128	20	428
nonsense	34	10				44
start loss						0
frameshift	56	19	3		1	79
inframe indel			10	1		11
splice donor/acceptor (+/-2bp)	5	7				12
splice region			9	17	1	27
non coding			47	71	69	187
Total	96	41	343	352	128

Highest pathogenic variant AF is 0.00000658

Variants in GLI3

This is a list of pathogenic ClinVar variants found in the GLI3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-41960961-G-T		Pallister-Hall syndrome • Polydactyly • Greig cephalopolysyndactyly syndrome	Uncertain significance (Jan 13, 2018)
7-41960988-A-AT		Polydactyly • Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome	Benign (May 12, 2021)
7-41961021-G-T		Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome • Polydactyly	Conflicting classifications of pathogenicity (Jan 13, 2018)
7-41961068-T-C		Polydactyly • Greig cephalopolysyndactyly syndrome • Pallister-Hall syndrome	Benign/Likely benign (May 12, 2021)
7-41961092-G-A		Polydactyly • Greig cephalopolysyndactyly syndrome • Pallister-Hall syndrome	Benign (Jan 12, 2018)
7-41961236-A-G		Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome • Polydactyly	Uncertain significance (Jan 13, 2018)
7-41961326-C-T		Greig cephalopolysyndactyly syndrome • Pallister-Hall syndrome • Polydactyly	Benign (Jan 13, 2018)
7-41961328-T-C		Polydactyly • Greig cephalopolysyndactyly syndrome	Uncertain significance (Jan 12, 2018)
7-41961469-A-C		Polydactyly • Greig cephalopolysyndactyly syndrome	Uncertain significance (Jan 12, 2018)
7-41961471-C-T			Benign (Sep 01, 2022)
7-41961573-G-A		Greig cephalopolysyndactyly syndrome • Polydactyly • Pallister-Hall syndrome	Benign (May 12, 2021)
7-41961586-A-C		Greig cephalopolysyndactyly syndrome • Polydactyly	Uncertain significance (Jan 12, 2018)
7-41961615-C-T		Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome • Polydactyly	Benign/Likely benign (May 15, 2021)
7-41961654-G-A		Greig cephalopolysyndactyly syndrome • Pallister-Hall syndrome • Polydactyly	Uncertain significance (Jan 12, 2018)
7-41961664-C-T		Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome • Polydactyly	Conflicting classifications of pathogenicity (Jul 01, 2022)
7-41961710-G-C		Polydactyly • Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome	Conflicting classifications of pathogenicity (Jan 13, 2018)
7-41961718-T-C		Polydactyly • Greig cephalopolysyndactyly syndrome	Uncertain significance (Jan 13, 2018)
7-41961813-C-T		Polydactyly • Greig cephalopolysyndactyly syndrome	Conflicting classifications of pathogenicity (Feb 01, 2023)
7-41961822-C-G		Greig cephalopolysyndactyly syndrome • Pallister-Hall syndrome • Polydactyly	Uncertain significance (Jan 13, 2018)
7-41961865-C-G		Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome • Polydactyly	Uncertain significance (Jan 12, 2018)
7-41961911-A-G		Greig cephalopolysyndactyly syndrome • Polydactyly • Pallister-Hall syndrome	Uncertain significance (Jan 12, 2018)
7-41961971-TA-T		Pallister-Hall syndrome • Polydactyly • Greig cephalopolysyndactyly syndrome	Conflicting classifications of pathogenicity (May 12, 2021)
7-41961971-T-TA			Likely benign (May 12, 2021)
7-41961973-A-T		Pallister-Hall syndrome • Greig cephalopolysyndactyly syndrome • Polydactyly	Benign/Likely benign (Mar 01, 2023)
7-41961983-G-T		Polydactyly • Greig cephalopolysyndactyly syndrome • Pallister-Hall syndrome	Likely benign (Apr 27, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GLI3	protein_coding	protein_coding	ENST00000395925	14	276922

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000122	125741	0	7	125748	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.522	932	978	0.953	0.0000656	10388
Missense in Polyphen		305	382.45	0.79748		4131
Synonymous	-2.02	480	427	1.12	0.0000344	3218
Loss of Function	6.17	5	53.8	0.0929	0.00000298	601

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000124	0.0000615
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000110	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.00000882	0.00000879
Middle Eastern	0.000110	0.000109
South Asian	0.0000654	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'. {ECO:0000269|PubMed:10693759, ECO:0000269|PubMed:11238441, ECO:0000269|PubMed:17764085}.
• Disease: DISEASE: Greig cephalo-poly-syndactyly syndrome (GCPS) [MIM:175700]: Autosomal dominant disorder affecting limb and craniofacial development. It is characterized by pre- and postaxial polydactyly, syndactyly of fingers and toes, macrocephaly and hypertelorism. {ECO:0000269|PubMed:10441342, ECO:0000269|PubMed:12414818, ECO:0000269|PubMed:12794692, ECO:0000269|PubMed:9302279}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pallister-Hall syndrome (PHS) [MIM:146510]: An autosomal dominant disorder characterized by a wide range of clinical manifestations. Clinical features include hypothalamic hamartoma, pituitary dysfunction, central or postaxial polydactyly, and syndactyly. Malformations are frequent in the viscera, e.g. anal atresia, bifid uvula, congenital heart malformations, pulmonary or renal dysplasia. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polydactyly, postaxial A1 (PAPA1) [MIM:174200]: A condition characterized by the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type A, the extra digit is well-formed and articulates with the fifth or a sixth metacarpal/metatarsal. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polydactyly, postaxial B (PAPB) [MIM:174200]: A condition characterized by an extra digit in the occurrence of supernumerary digits in the upper and/or lower extremities. In postaxial polydactyly type B the extra digit is not well formed and is frequently in the form of a skin. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polydactyly preaxial 4 (POP4) [MIM:174700]: Preaxial polydactyly (i.e., polydactyly on the radial/tibial side of the hand/foot) covers a heterogeneous group of entities. In preaxial polydactyly type IV, the thumb shows only the mildest degree of duplication, and syndactyly of various degrees affects fingers 3 and 4. {ECO:0000269|PubMed:10441570}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Basal cell carcinoma - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hedgehog signaling pathway - Homo sapiens (human);HH-Core;Ectoderm Differentiation;Tgif disruption of Shh signaling;Tumor suppressor activity of SMARCB1;Hedgehog Signaling Pathway;Hedgehog Signaling Pathway;Endochondral Ossification;RUNX2 regulates osteoblast differentiation;RUNX2 regulates bone development;Transcriptional regulation by RUNX2;Signal Transduction;Gene expression (Transcription);GLI3 is processed to GLI3R by the proteasome;Generic Transcription Pathway;Hedgehog;RNA Polymerase II Transcription;Hedgehog;Hedgehog ,off, state;GLI proteins bind promoters of Hh responsive genes to promote transcription;Hedgehog ,on, state;Signaling by Hedgehog;Hedgehog signaling events mediated by Gli proteins (Consensus)

Recessive Scores

• pRec: 0.107

Intolerance Scores

• loftool: 0.0146
• rvis_EVS: -1.31
• rvis_percentile_EVS: 4.83

Haploinsufficiency Scores

• pHI: 0.996
• hipred: Y
• hipred_score: 0.707
• ghis: 0.542

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.865

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gli3
• Phenotype: embryo phenotype; respiratory system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); pigmentation phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); hearing/vestibular/ear phenotype; vision/eye phenotype; skeleton phenotype; renal/urinary system phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); taste/olfaction phenotype; endocrine/exocrine gland phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: gli3
• Affected structure: spinal cord
• Phenotype tag: abnormal
• Phenotype quality: physical object quality

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;metanephros development;branching involved in ureteric bud morphogenesis;in utero embryonic development;positive regulation of neuroblast proliferation;smoothened signaling pathway;axon guidance;hindgut morphogenesis;heart development;negative regulation of cell population proliferation;anterior/posterior pattern specification;proximal/distal pattern formation;protein processing;optic nerve morphogenesis;hippocampus development;smoothened signaling pathway involved in ventral spinal cord interneuron specification;smoothened signaling pathway involved in spinal cord motor neuron cell fate specification;forebrain dorsal/ventral pattern formation;layer formation in cerebral cortex;forebrain radial glial cell differentiation;lateral ganglionic eminence cell proliferation;melanocyte differentiation;lung development;prostate gland development;positive regulation of chondrocyte differentiation;T cell differentiation in thymus;limb morphogenesis;wound healing;positive regulation of protein import into nucleus;odontogenesis of dentin-containing tooth;embryonic digit morphogenesis;negative regulation of apoptotic process;nose morphogenesis;tongue development;response to estrogen;negative thymic T cell selection;negative regulation of neuron differentiation;positive regulation of osteoblast differentiation;negative regulation of smoothened signaling pathway;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of alpha-beta T cell differentiation;negative regulation of alpha-beta T cell differentiation;embryonic digestive tract morphogenesis;embryonic digestive tract development;developmental growth;camera-type eye morphogenesis;embryonic skeletal system morphogenesis;oligodendrocyte differentiation;roof of mouth development;frontal suture morphogenesis;lambdoid suture morphogenesis;sagittal suture morphogenesis;mammary gland specification;smoothened signaling pathway involved in dorsal/ventral neural tube patterning;artery development;anterior semicircular canal development;lateral semicircular canal development;cell differentiation involved in kidney development;thymocyte apoptotic process;negative regulation of canonical Wnt signaling pathway;liver regeneration;regulation of bone development
• Cellular component: nucleus;nucleoplasm;cytoplasm;cytosol;cilium;axoneme;nuclear speck;transcriptional repressor complex;ciliary tip;ciliary base
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;chromatin binding;DNA-binding transcription factor activity;protein binding;beta-catenin binding;histone acetyltransferase binding;mediator complex binding;histone deacetylase binding;metal ion binding